GB1575156A

GB1575156A - Isoxazolylmethylbenzomorphans

Info

Publication number: GB1575156A
Application number: GB14796/78A
Authority: GB
Original assignee: CH Boehringer Sohn AG and Co KG; Boehringer Ingelheim GmbH
Current assignee: CH Boehringer Sohn AG and Co KG; Boehringer Ingelheim GmbH
Priority date: 1977-04-15
Filing date: 1978-04-14
Publication date: 1980-09-17
Also published as: US4133888A; FR2387228B1; DK144678B; GR64819B; CA1079726A; ZA782149B; AT360667B; ATA241978A; IE46722B1; NO148418C; ES472408A1; AU3509878A; ES468798A1; PH13854A; NL7803977A; DK144678C; ES472407A1; AT360666B; NO781310L; NO148418B

Description

PATENT SPECIFICATION ( 11) 1575156

( 21) Application No 14796/78 ( 22) Filed 14 April 1978 ( 31) Convention Application No2 716 687 ( 19), ( 32) Filed 15 April 1977 in ( 33) Fed Rep of Germany (DE) ( 44) Complete Specification published 17 Sept 1980 ( 51) INT CL 3 CO 7 D 413/06; A 61 K 31/435; (C 07 D 413/06, 221/26, 261/08) ( 52) Index at acceptance C 2 C 1370 1539 213 215 220 226 22 Y 247 250 251 25 Y 28 X 29 X 29 Y 30 Y 365 36 Y 509 50 Y 623 672 800 802 80 Y AA WE ( 72) Inventors HERBERT MERZ and KLAUS STOCKHAUS ( 54) ISOXAZOLYLMETHYLBENZOMORPHANS ( 71) We, BOEHRINGER INGELHEIM GMBH, a Body Corporate organised under the laws of the Federal Republic of Germany, of Ingelheim am Rhein, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be

performed, to be particularly described in and by the following statement:-

This invention relates to novel derivatives of 6,7-benzo-morphane having interesting pharmacological properties.

According to one feature of the present invention there are provided compounds of general formula N CH 2 N N (I) %R 1 HO (wherein R' represents a methyl, ethyl or propyl group; and R 2 represents a hydrogen atom or a methyl or ethyl group) and acid addition salts thereof.

When R 2 in the compounds according to the present invention represents an alkyl group, two diastereomeric classes of compounds are possible In compounds of the a-class, the groups R' and R 2 are in a cis-configuration, and in the p-class they are arranged in a trans-configuration As shown in the above formula 1, it is intended that only the compounds of the a-class are within the scope of the present invention.

It will be appreciated that compounds of general formula I may occur in the form of optical isomers and it is intended that racemates, laevorotatory and dextrorotatory optical isomers are within the scope of the present invention.

Compounds of general formula I according to the present invention possess interesting pharmacological properties In particular we have found that such compounds exhibit an activity upon the central nervous system and have analgesic and morphine-antagonistic properties.

Acid addition salts of compounds of general formula I for use in medicine should be physiologically acceptable acid addition salts Other acid addition salts may be of use, however, in the preparation of compounds of general formula I or of the physiologically acceptable acid addition salts thereof.

Preferred compounds of the invention by virtue of their favourable pharmacological properties are the 5,9-a-dialkyl-2 '-hydroxy-2-( 5isoxazolylmethyl)-6,7-benzomorphanes and their acid addition salts Especially preferred by R 2 2 1,575,156 2 virtue of its particularly favourable pharmacological properties is 5,9-adimethyl2 '-hydroxy-2-( 5-isoxazolylmethyl)-6,7-benzomorphane and its acid addition salts, and particularly the laevorotatory isomer thereof.

Compounds of general formula I may be prepared by the following processes, which processes constitute further features of the present invention: 5 a) By reacting a norbenzomorphane of formula -N-H 2 R 2 HO (wherein R' and R 2 are as hereinbefore defined) with a 5isoxazolylmethyl derivative of formula | z N (III) 10 1 0 j X-CH 2 (wherein X represents an anionically removeable group, such as for example a halogen atom, preferably a chlorine, bromine or iodine atom, or an arylsulfonyloxy or alkylsulfonyloxy group).

Due to its ready availability, 5-bromomethylisoxazole is especially preferred as the alkylating agent of formula III 15 In order to ensure full utilization of the rather expensive starting material of formula II, the alkylating agent of formula III is preferably used in stoichiometric quantities or in molar excess, and full reaction of the compound of formula II is generally achieved using a 10 %O molar excess.

If the acid, H-X, formed during the above reaction is sufficiently acidic to 20 cause salt formation with the norbenzomorphane of formula II, it is advantageous to perform the reaction in the presence of an acid-binding agent Inorganic or organic bases may be used for this purpose, examples being inorganic carbonates, hydrogen carbonates, oxides or hydroxides or organic amines Preferred are tertiary amines such as triethylamine and N,N-dicyclohexylethylamine and 25 inorganic compounds, in particular sodium hydrogen carbonate.

Although the use of a solvent in the above reaction is not essential, it is convenient and of advantage to effect the reaction in the presence of a solvent which is inert under the reaction conditions Solvents which may be used include, for example, hydrocarbons and halogenated hydrocarbons, alcohols, ketones, 30 ethers and aprotic solvents such as dimethylformamide and dimethylsulfoxide.

Solvents having a boiling point at a favourable reaction temperature are preferred, so that the reaction may be carried out under reflux Mixtures of dimethylformamide and tetrahydrofuran have proved to be especially suitable as solvents for the reaction 35 The reaction temperature may vary within broad limits, thus at too low a temperature, the reaction tends to take a long time, while at high temperatures the reaction may be accomplished by too many undesired side-reactions Reaction temperatures between 50 and 150 C are preferred.

b) By hydrolysing a compound of formula 40 N -CH 2 -+( R 2 (IV) 3 R RO O (wherein R' and R 2 are as hereinbefore defined and R 3 represents an acyl group, which may be an inorganic or preferably an organic acyl group) preferably under alkaline or, most preferably, acid conditions.

From practical considerations simple acyl groups, in particular acetyl or 5 benzoyl groups for R 3 in the compound of formula IV are preferred.

The hydrolysis may be effected according to various methods The simplest is the alkaline or, preferably, acid hydrolysis of the phenolic ester group The reaction is preferably performed in the presence of an aqueous or aqueousalcoholic solvent The reaction temperature, which may vary within wide limits, is 10 advantageously from 200 C to 1000 C.

c) By subjecting a compound of formula N N -CH 0 (V) R O (wherein R' and R 2 are as hereinbefore defined, and R 4 represents an alkyl, aralkyl or alkoxyalkyl group) to ether splitting R 4 is preferably a methyl, benzyl or 15 methoxymethyl group.

Ether splitting may be effected according to various processes, depending on the nature of the group R 4 and should be selected to ensure that the isoxazole ring remains intact Methoxymethyl groups, for example, may be split off by rection with dilute mineral acids, and methyl groups may be split off with concentrated 20 mineral acids, for example hydrobromic acid Ether splitting with boron tribromide is especially suitable The reaction is preferably effected at a temperature of 20 to 150 'C.

The reaction products obtained by any of the above processes a) to c) may be isolated according to known laboratory methods, and may be purified and 25 crystallized in the form of the free bases or salts thereof.

Starting compounds of general formulae II and III are known compounds.

Starting compounds of general formula IV and V may be obtained by alkylation of an O-acyl-norbenzomorphane or an O-alkyl-norbenzomorphane with a compound of formula III 30 Compounds of general formula I according to the invention in the form of free bases may be converted into corresponding acid addition salts (preferably physiologically acceptable) in the conventional way Acids which may be used for salt formation are, for example, mineral acids such as hydrochloric acid hydrobromic acid, hydriodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid and nitric 35 acid or organic acids such as acetic acid, propionic acid, butyric acid, valeric acid, I 1,575, 156 oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, pyruvic acid, tartaric acid, citric acid, malic acid, benzoic acid, phydroxybenzoic acid, salicylic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, ascorbic acid, 8-chlorotheophylline, methanesulfonic acid and ethanesulfonic acid.

The compounds according to the present invention exist in the form of optical isomers and racemates If individual optical isomers are desired, the above 5 processes may be effected using optically active starting materials Alternatively, racemates of the compounds of general formula I may be resolved into the individual optical isomers by conventional methods such as, for example, by chromatographic methods or by fractional crystallization.

As indicated above we have found that compounds of general formula I 10 according to the invention and their physiologically acceptable acid addition salts exhibit a therapeutic activity upon the central nervous system In particular compounds according to the invention which have been tested exhibit analgesic and morphine-antagonistic activities, which we have demonstrated in the mouse by the Writhing test and the Haffner test Such an agonistic-antagonistic activity 15 profile points to a lack of or a very low addiction potential, according to current theories Our finding that 5,9-a-dimethyl-2 '-hydroxy-2-( 5isoxazolylmethyl)-6,7benzomorphane is unable to suppress morphine withdrawal symptoms in addicted rats and monkeys points to the same conclusion With respect to analgesic activity and therapeutic ratio, the above mentioned compound has shown 20 superior properties in our tests to 2-furfuryl-2 '-hydroxy-5,9-a-dimethyl6,7-benzomorphane having a closely related structure We have found similar results in a comparison of the above compound according to the invention with the known compound, 2-( 3-methylfurfuryl)-2 '-hydroxy-5,9-a-dimethyl-6,7benzomorphane which moreover does not exhibit the desired antagonistic component Of the 25 currently available commercial analgesics, we have considered pentazocine as a comparative substance This compound incorporates the same benzomorphane nucleus as the compounds according to the invention and has a similar agonisticantagonistic profile of activities, but in its therapeutic ratio we have found it to be far inferior to the latter The following Table summarizes the relevant 30 pharmacological data for the above compounds and shows the improved characteristics of 5,9-a-dimethyl-2 '-hydroxy-2-( 5-isoxazolylmethyl)-6,7benzomorphane according to the present invention.

-N R' / \ CH 3 35 CH 3 HO in the form of the methanesulfonate salts 1,575,156 1,575,156 5 H 3 C Re _ 1 N i Penta/ /,p -H C-) -H) zocine -H Bc 2 2 Analgesia (Writhing-Test, 0 6 18 0 6 1 4 mouse, S C, ED 50 mg/kg) Morphine-antagonism 0 1 1 inactive 0 025 lmouse (Nalorphin=l)I Toxicity (mouse, s c, 1080 292 305 220 LD 50, mg/kg) Therapeutic index (LD 50/ED 50) 1800 16 508 157 According to a further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula I as hereinbefore defined or a physiologically acceptable acid addition salt thereof in association with a pharmaceutical carrier or excipient 5 The compositions according to the invention may be in a form suitable for oral, rectal or parenteral administration, such as, for example, in the form of tablets, capsules, suppositories, solutions, suspensions, emulsions, powders, granulates, syrups and forms adapted to provide a sustained release of active ingredient Such forms may be prepared in a manner conventional to the 10 pharmaceutical art.

If desired, the compositions according to the invention may be in dosage unit form, suitable dosages being for example 0 5 to 100 mg and preferably I to 20 mg of active ingredient.

The compositions according to the invention may, if desired, additionally 15 contain one or more further physiologically active ingredients such as, for example, sedatives, tranquillizers and hypnotics.

Tablets may comprise several layers Coated tablets may be produced corresponding to the above mentioned tablets by coating tablet cores produced analogously to the tablets with agents usually applied for tablet-coats, such as, for 20 example, polyvinylpyrrolidone, shellac, gum arabic, talcum, titanium dioxide or sugar.

For obtaining sustained release of active ingredient(s) or for avoiding incompatibilities, the core may also consist of several layers Similarly the tabletcoat may be made of several layers for obtaining sustained release, whereby the 25 excipients used for tablets may be used.

Syrups of the active ingredient(s) and/or combinations of active ingredients according to the invention may additionally comprise a sweetener such as saccharin, a cyclamate, glycerin or sugar, as well as an agent improving the taste, for example, flavourings such as vanillin or orange extract They may also comprise suspension auxiliaries or thickeners such as sodium carboxymethyl cellulose, 5 wetting agents, for example, condensation products of fatty alcohols with ethyleneoxide, or preservatives such as p-hydroxybenzoates.

Injectible solutions may be produced in the conventional way, for example with addition of preservatives such as p-hydroxybenzoates or stabilizers such as complexons, and then filled into injection vials or ampoules 10 Capsules containing the active ingredient(s) and/or combinations of active ingredients may be produced, for example, by admixing inert carriers such as lactose or sorbitol with the active ingredient(s) and filling the mixture into gelatin capsules.

Suppositories may be produced, for example, by admixing the active 15 ingredient(s) and/or combinations of active ingredients with conventional carriers such as for example neutral fats or polyethylene glycol and/or its derivatives.

The following Examples serve to illustrate the preparation of compounds of general formula I according to the invention and also pharmaceutical compositions containing them: 20 Example 1.

5,9-a-Dimethyl-2 '-hydroxy-2-( 5-isoxazolylmethyl)-6,7-benzomorphane (hydrobromide, base, methanesulfonate and hydrochloride) 19.6 g ( 0 09 mol) of 5,9-ao-dimethyl-2 '-hydroxy-6,7-benzomorphane, 11 8 g ( 0 135 mol) of sodium hydrogen carbonate and 16 2 g ( 0 10 mol) of 5bromo 25 methyl-isoxazole are refluxed together in a mixture of 120 ml dimethylformamide and 200 ml of tetrahydrofuran for 2 5 hours, while stirring The mixture of solvents is then evaporated off under reduced pressure (water-jet pump) finally with a bath temperature of 80 to 90 C The evaporation residue is shaken with 250 ml of chloroform and 150 ml of water After separation of the phases in a funnel, the 30 chloroform phase is washed twice with 150 ml of water, dried over sodium sulfate, treated with 5 g of active charcoal, filtered and evaporated under reduced pressure.

A brownish, syrupy evaporation residue is obtained ( 38 g), which is dissolved in 35 ml of ethanol and 7 0 ml of 68 % hydrobromic acid During crystallization of the hydrobromide of the title compound, stirring is effected until a thick crystal mass is 35 formed, which is kept at O C overnight The crystals are then removed by suction filtration, washed with a little ice-cold ethanol and dried, at first in air, and then in a drying cabinet with air circulation at 80 C 31 7 g ( 92 9 %) of 5,9-adimethyl-2 'hydroxy-2-( 5-isoxazolylmethyl)-6,7-benzomorphane hydrobromide with a melting point of 166 C are obtained Recrystallization from 100 ml of ethanol and 20 ml of 40 water (keeping at -20 C overnight, suction filtration and drying as above) yields 28.8 g of substance with a melting point of 167 C.

The hydrobromide ( 28 8 g = 0 076 mol) is dissolved in a mixture of 120 ml of methanol and 30 ml of water While stirring, the mixture is gradually (initially dropwise) admixed with 10 5 ml of concentrated ammonia, whereby the free base is 45 precipitated in crystalline form Subsequently, while stirring is continued, 90 ml of water are added and the solution is allowed to stand overnight at O C Then it is suction filtered and washed, first thoroughly with water, thereupon with 50 % methanol After being quickly suction filtered, it is dried in a drying cabinet with air circulation at 80 C 21 4 g ( 94 4 % referred to the initial hydrobromide) of 5,9-a-di 50 methyl-2 '-hydroxy-2-( 5-isoxazolylmethyl)-6,7-benzomorphane of melting point 145 to 147 C are obtained, the melting point remaining unchanged after recrystallization.

To the base ( 21 4 g = 0 072 mol) dissolved in 48 ml ethanol, is added 7 2 g ( 0 075 mol) of methanesulfonic acid From the solution there soon crystallizes the 55 methanesulfonate salt It is stirred until a thick crystal mass has formed, which is kept at O C overnight After suction filtration, washing with ethanol/ether ( 1:1) and drying, at first in air and then in a drying cabinet with air circulation at 80 C, there are obtained 28 0 g ( 98 6 % referred to the initial base) of 5,9-adimethyl-2 'hydroxy-2-( 5-isoxazolylmethyl)-6,7-benzomorphane methanesulfonate with a 60 melting point of 190-192 C, which melting point remains unchanged after recrystallization.

The base ( 1 5 g = 0 005 mol) is dissolved in 5 ml of ethanol and then 2 5 ml 2 5 N 1,575,156 ethanolic HCI is added The solution is admixed with absolute ether until turbidity just begins From the solution, crystallizes 5,9-a-dimethyl-2 '-hydroxy-2( 5-isoxazolylmethyl)-6,7-benzomorphane hydrochloride which is isolated as above described for the methanesulfonate Yield: 1 5 g ( 89 5 % referred to the initial base) melting point 214 C, which remains unchanged after recrystallization from 5 ethanol/ether.

Example la.

5,9-a-Dimethyl-2 '-hydroxy-2-( 5-isoxazolylmethyl)-6,7-benzomorphane hydrobromide As described in Example 1, the title compound is obtained from 2 17 g ( 0 01 10 mol) of 5,9-a-dimethyl-2 '-hydroxy-6,7-benzomorphane using 1 29 g ( 0 011 mol) of 5-chloromethylisoxazole, yield: 3 3 g ( 87 0 %), melting point: 166 C.

Example lb.

5,9-a-Dimethyl-2 '-hydroxy-2-( 5-isoxazolylmethyl)-6,7-benzomorphane hydrobro 15 mide 15 As described in Example 1, the title compound is obtained from 2 17 g ( 0 01 mol) of 5,9-a-dimethyl-2 '-hydroxy-6,7-benzomorphane using ethanol as the solvent in a yield of 3 1 g ( 81 9 %) and melting point 160 C, rising after recrystallization to 167 C.

Example lc.

5,9-a-Dimethyl-2 '-hydroxy-2-( 5-isoxazolylmethyl)-6,7-benzomorphane hydrobro 20 mide As described in Example 1, the title compound is obtained from 2 17 g ( 0 01 mol) of 5,9-a-dimethyl-2 '-hydroxy-6,7-benzomorphane using 0 8 g of sodium carbonate (instead of sodium hydrogen carbonate), in a yield of 3 3 g ( 87 2 %, melting point 159-160 C, which rises after recrystallization to 166-167 C 25 Example 2.

(-) 5,9 a Dimethyl 2 ' hydroxy 2 ( 5 isoxazolylmethyl) 6,7 benzomorphane methanesulfonate As described in Example 1, 13 9 g ( 0 064 mol) of (-)-5,9-a-dimethyl-2 'hydroxy-6,7-benzomorphane, 8 1 g ( 0 096 mol) of sodium hydrogen carbonate and 30 11.4 g ( 0 070 mol) of 5-bromomethyl-isoxazole are allowed to react The reaction product is isolated as indicated in Example 1 The syrupy evaporation residue of the chloroform extract ( 25 g) is dissolved in 40 ml of ethanol with addition of 6 8 g ( 0.07 mol) of methanesulfonic acid and the solution is admixed with 50 ml of ether.

Crystallization of the methanesulfonate salt begins immediately, and is aided by 35 stirring and completed by allowing the crystalline suspension to stand overnight at 0 C It is then removed by suction filtration, washed with ethanol/ether ( 1:1) and dried, at first in air, then in a drying cabinet at 80 C 19 8 g ( 78 4 %) of (-)-5,9-a-dimethyl-2 '-hydroxy-2-( 5-isoxazolylmethyl)-6,7-benzomorphane methanesulfonate are obtained, melting point 188-190 C After recrystallization from 40 ml of 40 ethanol and 30 ml of ether, the substance ( 17 8 g) has a melting point of 198-190 C lal 25 = -795 O o (c = 1, Me OH).

Example 3.

9 a Ethyl 2 'hydroxy 2 ( 5 isoxazolylmethyl) 5 methyl 6,7 benzomorphane methanesulfonate 45 1.74 g ( 0 0075 mol) of 9 a-ethyl-2 '-hydroxy-5-methyl-6,7-benzomorphane, 0 95 g ( 0 0113 mol) of sodium hydrogen carbonate and 1 34 g ( 0 0083 mol) of 5-bromomethyl-isoxazole are reacted and the product isolated as described in Example 1.

The syrupy evaporation residue of the chloroform extract is treated with 50 ml of ether and insoluble side-products are separated by decanting the ether solution 50 The latter is evaporated and the residue crystallized as the methanesulfonate salt, analogously to Example 2 2 0 g ( 65 4 %) of 9-a-ethyl-2 '-hydroxy-2-( 5isoxazolylmethyl)-5-methyl-6,7-benzomorphane methanesulfonate are obtained, melting point 188-190 C After recrystallization from methanol/ether the substance ( 1 7 g) melts at 188-191 C 55 Example 4.

Ethyl 2 ' hydroxy 2 ( 5isoxazolylmethyl) 9 a methyl 6,7 benzomorphane methanesulfonate 1.74 g ( 0 0075 mol) of 5-ethyl-2 '-hydroxy-9-a-methyl-6,7-benzomorphane, 0 95 1.575,156 g ( 0 0113 mol) of sodium hydrogen carbonate and 1 34 g ( 0 0083 mol) of 5-bromoethyl-isoxazole are reacted and the product isolated analogously to Example 3, the product crystallizes as the methanesulfonate salt 2 2 g ( 71 9 %) of 5ethyl-2 'hydroxy-2-( 5-isoxazolylmethyl)-6,7-benzomorphane methanesulfonate are obtained, melting point 211-213 C After recrystallization from methanol/ether the substance ( 2 0 g) has a melting point of 211 to 213 C.

Example 5.

5,9 a Diethyl 2 ' hydroxy 2 ( 5 isoxazolylmethyl) 6,7 benzomorphane methanesulfonate 1 84 g ( 0 0075 mol) of 5,9-a-diethyl-2 '-hydroxy-6,7-benzomorphane, 0 95 g 10 ( 0.0113 mol) of sodium hydrogen carbonate and 1 34 g ( 0 0083 mol) of 5bromomethyl-isoxazole are reacted and the product isolated, analogously to Example 3, this product crystallizes as the methanesulfonate salt 2 0 g ( 63 1 %) of 5,9a-diethyl-2 'hydroxy-2-( 5-isoxazolylmethyl)-6,7-benzomorphane methanesulfonate are obtained Melting point 180-182 C, which remains unchanged after 15 recrystallization from methanol/ether.

Example 6.

2 'Hydroxy 2 ( 5 isoxazolylmethyl) S methyl 6,7 benzomorphane hydrochloride 1 53 g ( 0 0075 mol) of 2 '-hydroxy-5-methyl-6,7-benzomorphane 0 95 g ( 0 0113 20 mol) of sodium hydrogen carbonate and 1 34 g ( 0 0083 mol) of 5bromomethylisoxazole are reacted and the product isolated, analogously to Example 1 The syrupy evaporation residue of the chloroform extract is dissolved in 5 ml of ethanol with addition of 3 ml of 2 5 N ethanolic HC 1 and the solution is admixed with ether until it becomes just turbid From the solution, 2 '-hydroxy-2-( 5isoxazolylmethyl)-5 25 methyl-6,7-benzomorphane hydrochloride ( 1 7 g = 94 4 %) crystallizes with a melting point of 211 C, which does not change after recrystallization.

Example 7.

Ethyl 2 ' hydroxy 2 (isoxazolylmethyl) 6,7 benzomorphane 1 63 g ( 0 0075 mol) of 5-ethyl-2 '-hydroxy-6,7-benzomorphane, 0 95 g ( 0 0113 30 mol) of sodium hydrogen carbonate and 1 34 g ( 0 0083 mol) of 5bromomethylisoxazole are reacted and the product isolated analogously to Example 1 The evaporation residue of the chloroform extract is crystallized from 10 ml of ether together with I ml of acetone After drying the crystals at 80 C, there are obtained 1 5 g of 5-ethyl-2 '-hydroxy-2-( 5-isoxazolylmethyl)-6,7-benzomorphane The 35 substance is dissolved in about 80 ml of ethyl acetate and the solution is treated with active charcoal for further purification After filtering off the charcoal, the filtrate is evaporated down to about 10 ml From this concentrated solution the pure substance crystallizes ( 1 15 g = 54 % 0) with a melting point of 186-188 C.

Example 8 40

2 ' Hydroxy 2 ( 5 isoxazolylmethyl) 5 (n propyl) 6,7 benzomorphane As described in Example 6, the title compound is obtained from 1 74 g ( 0 0075 mol) of 2 '-hydroxy-5-(n-propyl)-6,7-benzomorphane, 0 95 g ( 0 0113 mol) of sodium hydrogen carbonate and 1 34 g ( 0 0083 mol) of 5-bromomethylisoxazole Yield: 1 2 g (= 53 8 %), melting point 178 C 45 Example 9.

5,9 a Dimethyl 2 ' Hydroxy 2 ( 5 isoxazolylmethyl) 6,7 benzomorphane methanesulfonate a) 2 'Benzoyloxy 5,9 a dimethyl 2 ( 5 isoxazolylmethyl) 6,7 benzomorphane 50 Analogously to Example 1, the title compound is obtained by reacting 2 'benzoyloxy-5,9-a-dimethyl-6,7-benzomorphane with 5-bromomethyl-isoxazole, and isolated as the evaporation residue of the chloroform extract and recrystallized from acetone/petroleum ether in the manner described Melting point, 138 C.

b) 5,9 a Dimethyl 2 'hydroxy 2 ( 5 isoxazolylmethyl) 6,7 benzomor 55 phane methanesulfonate 0.4 g of 2 '-benzoyloxy-5,9-a-dimethyl-2-( 5-isoxazolylmethyl)-6,7-benzomorphane ( 1 0 mmol) are dissolved in 30 ml of methanol The solution is admixed with 0 75 ml of 2 N Na OH and refluxed for 30 minutes It is then evaporated in vacuo and the residue is shaken with 25 ml of water, 5 ml of 2 N ammonium chloride and 60 ml of chloroform After separation of the phases in a funnel, the aqueous 1.575 156 solution is extracted once more with 10 ml of chloroform The combined chloroform extracts are washed with water, dried with sodium sulfate and evaporated in vacuo Analogously to Example 2, the evaporation residue is crystallized as the methanesulfonate salt The title compound is obtained in a yield of 0 21 g ( 53 3 %) and has a melting point of 188 5 C.

Example 10.

5,9 a Dimethyl 2 ' hydroxy 2 ( 5 isoxazolylmethyl) 6,7 benzomorphane a) 2 'Acetoxy 5,9 a dimethyl 2 ( 5 isoxazolylmethyl) 6,7 benzomorphane methanesulfonate Analogously to Example 2, the title compound is obtained by reacting 2 ' 10 acetoxy-5,9-a-dimethyl-6,7-benzomorphane with 5-bromomethyl-isoxazole and crystallizing the reaction product, m p 220 C.

b) 5,9 a Dimethyl 2 ' hydroxy 2 ( 5 isoxazolylmethyl) 6,7 benzomorphane 0 2 g ( 0 46 mmol) of 2 '-acetoxy-5,9-a-dimethyl-2-( 5-isoxazolylmethyl)6,7 15 benzomorphane methanesulfonate are refluxed with 10 ml of 2 N HCI for 30 minutes After cooling, the reaction solution is diluted with 8 ml of methanol and admixed with conc ammonia dropwise while stirring As a result, the title compound crystallizes out After standing overnight at O C, it is removed by suction filtration, washed with water and dried at 80 C 0 12 g ( 87 6 %) of 5,9-a-dimethyl-2 '-hydroxy 20 2-( 5-isoxazolylmethyl)-6,7-benzomorphane of melting point 144 C are obtained, after recrystallization from aqueous methanol the melting point rises to 145-146 C.

Example 11.

5,9 a Dimethyl 2 ' hydroxy 2 ( 5 isoxazolylmethyl) 6,7 benzomorphane 25 methanesulfonate a) 5,9 a Dimethyl 2 ( 5 isoxazolylmethyl) 2 ' methoxy 6,7 benzomorphane hydrochloride As described in Example 1, the title compound is obtained by reacting 5,9a-dimethyl-2 '-methoxy-6,7-benzomorphane with 5-bromomethyl-isoxazole, and is 30 crystallized as the hydrochloride salt and melts at 192 C after recrystallization from methanol/water/ether.

b) 5,9 a Dimethyl 2 'hydroxy 2 ( 5 isoxazolylmethyl) 6,7 benzomorphane hydrobromide 0 2 g ( 0 58 mmol) of 5,9-a-dimethyl-2-( 5-isoxazolylmethyl)-2 '-methoxy6,7 35 benzomorphane hydrochloride are dissolved in 2 5 ml of chloroform At 20 C while stirring the solution is admixed with 1 0 g of boron tribromide and the reaction mixture is allowed to stand for 15 minutes at room temperature It is admixed with 20 g of ice and 2 ml of conc ammonia and a further 25 ml of conc.

ammonia and then separated in a funnel after shaking The aqueous phase is 40 extracted with a further 10 ml of chloroform After washing with water and drying with sodium sulfate the combined chloroform extracts are evaporated in vacuo The residue is crystallized as the hydrobromide salt, as described in Example 1 Yield:

0.16 g = 72 7 %, melting point 167 C.

Example A: Tablets 45 Active ingredient according to the present invention 20 0 mg lactose 120 0 mg corn starch 50 0 mg colloidal silicic acid 2 0 mg soluble starch 5 0 mg 50 magnesium stearate 3 0 mg 0 mg The active ingredient is admixed with a portion of the excipients and granulated with a solution of the soluble starch in water After drying the granulate, 1,575,156 1,575,156 10 the remaining excipients are admixed and the mixture is pressed to tablets.

Example B: Coated Tablets. Active ingredient according to present invention 15 0 mg

lactose 100 0 mg corn starch 95 0 mg 5 colloidal silicic acid 2 0 mg soluble starch 5 0 mg magnesium stearate 3 0 mg 220 0 mg The active ingredient and excipients are pressed into tablet cores as described 10 in Example A, the cores are coated with sugar, talcum and gum arabic in the conventional way.

Example C: Suppositories.

Active ingredient according to present invention 10 0 mg lactose 150 0 mg 15 suppository mass q s, ad 1 7 g The active ingredient and lactose are admixed and the mixture is hcmogeneously suspended in the molten suppository mass The suspension is poured into cooled moulds to form suppositories of 1 7 g weight.

Example D: Ampoules 20 Active ingredient according to present invention 1 0 mg sodium chloride 10 0 mg double distilled water q sad 1 0 ml The active ingredient and sodium chloride are dissolved in the double distilled water and the solution is filled into ampoules under sterile conditions 25 Example E: Drops.

Active ingredient according to present invention 0 70 g methyl p-hydroxybenzoate 0 07 g propylp-hydroxybenzoate 0 03 g demineralized water q s ad 100 00 ml 30 The active ingredient and the preservatives are dissolved in demineralized water and the solution is filtered and filled into bottles, each of 100 ml capacity.

Claims

WHAT WE CLAIM IS:-

1 Compounds of general formula N CH 2 /< 2 =/v R 1 (I) R HO (wherein R' represents a methyl, ethyl or propyl group; and R 2 represents a hydrogen atom or a methyl or ethyl group) and acid addition salts thereof 2 5,9 a Dialkyl 2 ' hydroxy 2 ( 5isoxazolylmethyl) 6,7 benzomorphanes and acid addition salts thereof.

3 5,9 a Dimethyl 2 ' hydroxy 2 ( 5 isoxazolylmethyl) 6,7 benzomorphane and acid addition salts thereof.

4 (-) 5,9 a Dimethyl 2 ' hydroxy 2 ( 5isoxazolylmethyl) 6,7 benzo 10 morphane and acid addition salts thereof.

Compounds as defined in claim I as herein specifically disclosed with the exception of the compounds claimed in either of claims 3 and 4.

6 A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a norbenzomorphane of formula 15 -N-H (II) H O (wherein R' and R 2 are as defined in claim 1) with a 5-isoxazolylmethyl derivative of formula N X-CH 2 (Il I) (wherein X represents an anionically removeable group) 20 7 A process as claimed in claim 6 wherein a compound of formula III is used in which X represents a halogen atom or an arylsulfonyloxy or alkylsulfonyloxy group.

8 A process as claimed in claim 7 wherein a compound of formula III is used in which X represents a chlorine, bromine or iodine atom.

9 A process as claimed in any of claims 6 to 8 wherein the compound of 25 formula III is 5-bromomethyl-isoxazole.

1,1 1,,575,156 A process as claimed in any of claims 6 to 9 wherein the compound of formula III is present in molar excess.

11 A process as claimed in any of claims 6 to 10 wherein the reaction is effected in the presence of an acid-binding agent.

12 A process as claimed in claim 11 wherein the acid-binding agent comprises 5 triethylamine, N,N-dicyclohexylethylamine or sodium hydrogen carbonate.

13 A process as claimed in any of claims 6 to 12 wherein the reaction is effected in the presence of a solvent which is inert under the reaction conditions.

14 A process as claimed in claim 13 wherein the solvent comprises a hydrocarbon, halogenated hydrocarbon, alcohol, ketone or ether or an aprotic solvent 10 A process as claimed in claim 13 wherein the solvent comprises a mixture of dimethylformamide and tetrahydrofuran.

16 A process as claimed in any of claims 6 to 15 wherein the reaction is effected at a temperature between 50 and 150 'C.

17 A process for the preparation of compounds of general formula I as 15 defined in claim 1 which comprises hydrolysing a compound of formula N -CH R 2 (IV) / 'R 1 3 R R 30 (wherein R' and R 2 are as defined in claim I and R 3 represents an inorganic or organic acyl group).

18 A process as claimed in claim 17 wherein the hydrolysis is effected under 20 alkaline or acid conditions.

19 A process as claimed in either of claims 17 and 18 wherein a compound of formula IV is used in whichf R 3 represents an acetyl or benzoyl group.

A process as claimed in of claims 17 to 19 wherein the hydrolysis is effected in the presence of an aqueous or aqueous-alcholic solvent 25 21 A process as claimed in any of claims 17 to 21 wherein the reaction is effected at a temperature of from 20 to 1000 C.

22 A process for the preparation of compounds of general formula I as defined in claim 1 which comprises subjecting a compound of formula N CH 1 N X 2 \oz 30 (V) 4 \ RO (wherein R' and R 2 are as defined in claim 1, and R 4 represents an alkyl, aralkyl or alkoxyalkyl group) to ether splitting.

23 A process as claimed in claim 22 wherein a compound of formula V is used in which R 4 represents a methyl, benzyl or methoxymethyl group.

24 A process as claimed in either of claims 22 and 23 wherein the ether 35 splitting is effected by reaction with boron tribromide.

A process as claimed in claim 23 wherein a compound of formula V is used in which R 4 represents a methoxymethyl group and the ether splitting is effected by reaction with a dilute mineral acid.

I 1,575,156 1.575156 A process as claimed in claim 23 wherein a 'compound of formula V is used in which R 4 represents a methyl group and the ether splitting is effected by reaction with a concentrated mineral acid.

27 A process as claimed in any of claims 22 to 26 wherein the reaction is S, effected at a temperature of 20 to 1501 C 5 28 A process as claimed in any of claims 6 to 27 wherein a compound of formula I is first produced and is converted into an acid addition salt thereof.

29 A process as claimed in any of claims 6 to 28 for the preparation of compounds as claimed in claim I in optical isomer form, which comprises effecting the reaction using an optically active starting material or resolving a racemate of 10 the compound of formula I or an acid addition salt thereof first produced into its individual optical isomers.

A process as claimed in any of claims 6 to 29 substantially as herein described.

31 A process for the preparation of compounds as defined in claim I 15 substantially as herein described in any of Examples 1 to 11.

32 A compound as claimed in claim 1 whenever prepared by a process as claimed in any of claims 6 to 31.

33 Pharmaceutical compositions comprising as active ingredient at least one compound of formula I as defined in claim 1 or a physiologically acceptable acid 20 addition salt thereof in association with a pharmaceutical carrier or excipient.

34 Compositions as claimed in claim 33 in a form suitable for oral, rectal or parenteral administration.

Compositions as claimed in claim 34 in the form of tablets, capsules, suppositories, solutions, suspensions, emulsions, powders, granulates, syrups or 25 forms adapted to provide a sustained release of active ingredient.

36 Compositions as claimed in any of claims 33 to 35 in the form of dosage units.

37 Compositions as claimed in claim 36 wherein each dosage unit contains from 0 5 to 100 mg of said active ingredient 30 38 Compositions as claimed in claim 37 wherein each dosage unit contains from 1 to 20 mg of said active ingredient.

39 Compositions as claimed in any of claims 33 to 38 additionally containing at least one further physiologically active ingredient.

40 Compositions as claimed in claim 39 wherein the further active ingredient 35 is selected from sedatives, tranquillizers and hypnotics.

41 Compositions as claimed in claim 33 substantially as herein described.

42 Pharmaceutical compositions comprising as active ingredient a compound of formula I as defined in claim 1 or a physiologically acceptable acid addition salt thereof substantially as herein described in any of Example A to E 40 For the Applicants, FRANK B DEHN & CO, Chartered Patent Agents, Imperial House, 15-19, Kingsway, London, W C 2.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1980.

Published by the Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.

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